Cell growth and cell death are programmed and the precise timing of each of the programs is a critical factor in the life or death of the cells of our body. Each of these life/death programs for each person is unique. This uniqueness is due, largely, in the way in which each of our genes; with their multiple mutations break and recombines together. It is the interaction of these genomes (genes) and our changing environments that will inevitably lead to the dysregulation of these multiple timing devices of all our cell types which must be maintained to protect the very delicate balance between cell growth and cell death. All of the cell types in our body grow and die at very different rates and therefore a huge number of timing devices are required to maintain homeostasis (life/death balance) between all of these different cell types. Moreover, some individual cell types survive only for a few hours while other cell types survive for years. The maintenance and regulation of this delicate balance is most difficult for the immune system (cell survival measured in hours and the nervous system (cell survival measured in years). The immune system must rapidly mobilize and proliferate in response to inflammation but it just as rapidly must demobilize and the cells must die once the crisis is past, the invaders destroyed, digested and their foreign residues are excreted or properly stored. Similarly, while the nervous system must rapidly process all incoming information and store this information or relay it to other cell in the organism. It is precisely the storage and retrieval process of the nervous system that mandates that the cells survive for years. When any toxic or metabolic mishap appears in the immune system or nervous system, then one or more programmed death programs becomes dominant.
In this age of increased communication and heightened changing environmental perturbations, these two critical systems are overworked and apt to either misread the incoming information or fail to respond to the information properly. The result is the development of symptomatic disease of multiple types and this is dependent upon the type of stress and the individual; genetic weak points that are present in our unique genomes. In most cases, death occurs, with the resultant swelling of their membrane-bound cytoplasmic granules, mitochondria and fragmentation and condensation of the nucleus. This is called apoptosis. However, occasionally, a rare over stressed cell learns how to suppress or knock out their programmed cell death, survive and amplify their own growth programs. The end result is an immortal cell, cancer.
Thus, it appears that stress induced changes in the delicate balance between cell life and cell death appears to be responsible for the chronic conditions in which the timing for cell proliferation vs. cell death becomes imbalanced and either the chronic loss or excessive accumulation of uncontrolled cells is the end result. Therefore, there are two major factors in the development of chronic diseases.
1. Stressors. These include food, especially calories or oxidants and various poisons (physical, immunologic, psychic, chemical, bacteriologic, parasitic or viral, and behavioral). The specific amount (dose) of stress that is intolerable for each specific individual must be identified.
2. Genetic weak links. These genetic factors which are responsible for the development of chronic disease are biologically trivial and, therefore, usually bypassable. Since, our over-stressed genomes have developed many routes or devices which can wither repair or develop alternate routes that bypass for the minor damages. However, in order for these alternative pathways to operate, different signals must be obtained from the living cell.
Syndromes Associated With Stressors
1. Caloric Imbalance. Calories, like all growth factors for cells, are potent activators if cell death when they are deficient (too little) or in excess (too much). When calories in excess are provided, the over worked adipocytes (fat cells), pancreatic insulin secreting cells and vascular epithelium (blood vessel lining cells) die while conversely, the cells of the colon, breast, vascular phagocytes are forced to grow excessively. The delayed symptoms that may appear include those of diabetes, fat cell death, vascular obstructions (heart and brain), immune or cerebral dysfunction and excessive cellular proliferation (cancer). The constellation of genetic weak links in each unique individual determine both the specific breaking point and the target organ system.
In the experimental model, when rodents who are deprived of motivation and supplied with an excess of food, their normal pathways that are responsible for controlling energy intake, energy usage and energy storage rapidly falter. These rodents soon degenerate. Obesity, diabetes, occluded blood vessels and excretory ducts and dysregulated cells growth disease and senility soon emerge. Not surprisingly, removal of the excess food (calories) stress prevents all of these random losses of cellular functions, including the late developing cancers. These murine experiments in caloric glut teach us that a global stress, such as energy excess, which in time results in multiple breakdowns in most of the control pathways, can be prevented by simply removing the causative energy stress plus adding a motivational component, hunger.
Undoubtably, the removal of the caloric glut along with application of living motivations in humans will slow the loss of many of our degenerating cells, especially of those cells which control our energy metabolism. However, in long lived humans, successful prevention of chronic slowly progressive cell loss/overproductive syndromes, such as atherosclerosis and cancer is difficult because it is not currently detectable at the early dpe-dysfunctional stages of the disease. Thus, to prevent these later cell losses, early detection methods are required. To perfect and quantitate such detection methods is our initial objective. Quantification is essential since each individual is unique and his response to his individual stress is also unique.
2. Oxygen. Oxygen, like calories is a potent and essential growth factor, which when taken in excess or is deficient , is rapidly fatal. When totally deficient, neurons die in 3-5 minutes and when in excess, the lining cells of the lung die within a few hours. In the metabolic consumption of calories, electrons are liberated and are capable of destroying cellular enzymes, cellular membranes (lipids and lipoproteins) as well as cellular genome (nuclear DNA). Oxygen or other electron acceptors must be available intracellularly in the appropriate amounts and the appropriate time. Furthermore, enzymes which allow oxygen to accept two electrons rather than only one must always be present and capable of functioning rapidly, especially when calories are in excess. Because superoxide and peroxide act as potential growth factors as well as potential poisons, the end result of their excess is a dysregulated oxygen metabolism which may lead to either a degenerative or proliferative disease, depending upon the genetic constitution of the individual.
3. Drugs and Addiction. Drugs, notably tobacco and alcohol damage the cellular life/death regulating systems. Some cells proliferate excessively while the cells die and disappear. The extent of the changes in the life/death homeostatic cellular programs depends upon the individual weak links that are present in the specific cell type of each individual as well as the dose (potency) and timing of the dysregulating drug. Tobacco smoke affects the lining cells of the lungs that are necessary for the transport of oxygen and carbon dioxide into and out of the blood. Alcohol may poison the liver and a protective overgrowth of fibroblasts follow hepatocyte death.
4. Environmental Toxins. Solvents, gases, hydrocarbons, oxidants, heavy metals and many others, all effect the genetically weak link and thus are related to a dysfunction in the life/death cycle.
5. Viruses
A. The herpes virus group (herpes, Epstein Barr and other DNA viruses) lives in human cells. The prostate is commonly infected and the virus is present in the semen. The virus may cause cellar overgrowth by inhibiting one of our natural protective growth inhibitors (tumor suppressor gene, called P53) which normally inhibits cellular overgrowth. Without this effective inhibitor, the deficient cells rapidly out grow its neighboring cells and ultimately kill the surrounding cells by usurping the neighboring cells nutrition.
B. Murine retroviral model of neuro-immuno-degeneration. Injections of a murine virus, Ts1, into newborn mice results in a loss of specific immune cells and neurons with an overgrowth of astocytes in the brain in 3-5 weeks. If the animals survives the early immune and nerve cell loss, tumors of the immune system and the nervous system develop. The Ts1 virus enters its target cell by binding with the surface receptor that normally transports basic amino acids into the cell. The infected cell either multiply and produce defensive molecules or die. If the viral load is large and completely occupies all of the amino acid transporter sites on the cell membrane, the cell will either starve to death due to lack of the essential basic amino acids, especially arginine, or it will activate one of its death programs. Arginine is one of the essential amino acids that is required to produce polyamines, e.g., spermine, which amines are essential for structural integrity of the nucleus. In this murine model, the ensuing amino acid deficiencies are the crucial death factor and the predicted death may be prevented by supplying the deficient amino acids in amounts large enough to compete with the virus for transport into the cell. Furthermore, the excess amino acids that bind to the transporter will deny entrance of the virus into the cells and are potent protector agents. Moreover, in this model with imbalanced cell growth/death programs, then immune and nervous system modulators, nutritionals, anti-oxidative preventive therapies have proved to be a successful combination therapy.
Genetic Imbalance: Syndromes in which the Weak Links are Known
It is because each of us possesses unique gene pools which harbor multiple mutations that each, under stress, may activate signals which program cellular death. Therefore, we are all vulnerable to life's many stresses, especially stresses that may perturb electron flow, such as Down's Syndrome or amyotrophic lateral sclerosis syndromes (ALS). In Down's Syndrome trisomy 21, in which genes that control oxidative metabolism are imbalanced, the cell death programs, especially in the brain, are very labile and easily perturbated by most stresses. In ALS syndrome in which a major gene involved in the electron transfer (superoxide dismutase) is mutated, electron flow becomes dysregulated, especially in the very active RNA rich motor neurons. The result is that the cell death pathways are again activated and these neurons slowly degenerate.
In syndromes in which the genes that control the timing for the major activities of cells, i.e., cellular growth, death, differentiation and repair, mutagens which disrupt or imbalance these carefuilly orchestrated timing genes lead to the production of ill-formed cells with defective parts and limited survival. This fate leading to premature death is especially prominate in cells which must rapidly reproduce under stress and also must as rapidly die, such as most cells of the immune system. This type of premature death also awaits those neurons which must continuously produce and maintain cell parts, i.e., synapses and dendrites, and are, therefore, more susceptible to oxidative or metabolic stresses.
1. Ataxia Telangiectasia (AT)
AT is a syndrome in which certain cells in the immune and nervous system fail to mature properly and are eventually lost. A defective gene has been identified and it appears to function as a modulator or switching box for directing the cellular life/death process in the thymus derived T and B cells, cerebellar neurons and in some vascular cells. The result is immune deficiency, ataxia and deformed dilated blood vessels. AT is a recessive genetic disorder of childhood that occurs in one in 40,000 to 100,000 persons worldwide. At least 10% of AT patients develop cancer of the lymphoid tissues, stomach, brain, breast, skin, parotid gland, liver, larynx and ovaries. The location of the ATM gene on Chromosome 11q22-23. AT cells show increased chromosomal breakage, telomere shortening and elevated intrachromosomal recombination and are hypersensitive to ionizing radiation and radiomimetic chemicals. In ataxia telangiectasia, in which the ATN gene is mutated and fails to efficiently upregulate the major timing gene, p53, the premature death of immune cells and susceptible neurons is the end result. In those few immature cells in the thymus gland which manage to adapt to their missing timing gene (ATM), and continue to grow uncontrollably, thymic cancer in the absence of any other cancer is the end result. Furthermore, in mice, in which the ATM gene is completely knocked out, all homogenous mice, which are normal at birth, die of the thymic cancer by 4 months of age.
Since mice lacking the ATM gene from conception grow and develop normally until the thymic tumor intervenes, and since no cells other than the immature lymphocytes in the thymus either die or become cancerous, it is clear that the timing function of the ATM gene product is critical only in cells which must respond defensively to environmental stresses induced by living, i.e., cells involved in postnatal learning, immune defense and postnatal reproduction. The rapidly dividing living cells in the intestines do not degenerate but do lose their ability to defend themselves against radiant energies.
Other gene products which may disrupt the delicate balance in the cell growth and cell death pathways are abundant in man and include the presenilin genes in Alzheimer's Syndrome, the telomere genes in Huntington's Disease or AIDs, or the Fas, Fas ligands genes in murine autoimmune syndrome. In all of these syndromes, the dysregulation in the cell growth/cell death pathways leads to either excessive cell growth or to accelerated cell death, depending upon the presence of alternate or bypass pathways in the specific cell. For example, when various stresses are directed toward the central nervous system, neurons will degenerate while their more numerous support or helper cells will adapt and finally proliferate.
Progressive cerebellar ataxia and progressive oculocutaneous telangiectases appear at the ages of 2-6 in the affected children. Elevated serum alphafetoprotein and plasma carcinoembryonic antigen combined with low levels of IgA and/or IgE provide the laboratory basis for the clinical picture of AT.
2. Down's Syndrome (Trisomy 21)
One extra chromosome is present and too much DNA is present in each cell and the resultant dysregulated signaling also leads to either cell death or uncontrolled cell growth. The premature neuronal cell death in Down's Syndrome can be completely prevented, in vitro, by supplying the cells with extra reductants and/or antioxidants. Thus, although the precise function of all the excess normal genetic material is not known, it is clear that the loss of neurons is due at least in part either to a deficiency in reductive energy or to an excess of oxidizing power. The extra copy of chromosome 21 may lead to the development of Alzheimer's/Parkinson's Disease pathology is that the gene leads to the over production of amyloid and the accumulation of senile plaques,
3. Cancer
Cancer is an imbalance of Life/Death programs:
a. Life/death balancing factors in which stimulators such as c-mye, cyclin, D1, AP-1, Il-2, and E1A, TGFa are opposed by P21, p53, Rb, Fas, Stromelysin and TGFb. PA1 b. Energy Homeostasis (calories, fatty acids, etc.) PA1 c. Redox Homeostasis (cysteine, NO) PA1 d. Proteolysis Homeostasis (Ice, CPP32, Stromelysin) PA1 e. Nutrient Homeostasis(choline, arginine) PA1 f. Transport Homeostasis PA1 g. Nuclear Structure Homeostasis PA1 h. Basal Membrane Homeostasis (differentiation, apoptosis) PA1 i. Plasma Membrane Homeostasis (ligands, matrix, signal transduction) PA1 j. Cell Cycling Homeostasis (Cyclin, p21, c-myc, WAF1, ICE) PA1 k. Basement Membrane (Matrix) Homeostasis.
The C-myc primary gene which is responsible for maintaining the cellular life/death balance, while Cyclin-D1 is an enzyme that is required during mitosis. E1, AP1, TGFs, IL-2 and the basement membrane are some of the known growth factors which are required for cells to grow and differentiate into mature cells. P21, p53, Rb, Fas, TGFb are factors that stop cellular growth and cellular cycling. Stromelysin is a proteolytic enzyme that destroys the basement membrane and thus removes the major required for cell differentiation. Spermine is a highly charged growth factor which is used to stabilize the ever changing structure of DNA and various other structural proteins and lipids. p34 is a factor required to stabilize the nuclear components to be reproduced during cell cycling (mitosis).
Signal Transduction Imbalances
Viruses, which must bind to specific receptors or transporters on the surface of cells for entry and exit from specific cells and they also must usurp the cell's growth machinery for its own parasitic reproduction and will eventually perturb the cell's growth/death pathways with subsequent uncontrolled cell growth and/or cell death.
Viruses also disrupt cellular growth/death pathways by inserting their own promotional genes into inappropriate locals in the host DNA. This insert, like other agents which may oxidize or change or damage host DNA, may activate the cell death pathways. Such activated pathways may be beneficial in the sense that unwonted viruses or cancerous cells or overactive destructible inflammatory cells can be eliminated. But perturbation of this cell destruction process will in time result in the cell loss syndromes as seen in neuro-immuno-degenerative disorders or aging.
There examples suggest that most of our current chronic ills result form aberrant signals induced by mutated genes or destructive environmental cues which perturb timing of the cell growth/cell death pathways. These examples also suggest that if counter signals which can rebalance these uncontrolled pathways were available, most of our degenerative and neoplastic illnesses could be avoided.